Medical Design Technology®
precedents and the respective FDA office
with the most experience for the product
in question.

2. Research the global regulatory
guidelines. Though the FDA path for
combination product regulatory approval
is more defined and currently evolving,
there is little harmonization with the rest
of world. For example, if a sponsor wanted
to file for market approval in Europe, there
is no specific, centralized decision-making
body to provide a clear understanding of
filing requirements. For Europe, MEDDEV

2.1/3 establishes clinical data submission
considerations, but falls short in describing
the clear regulatory path the product must
progress through to obtain a favorable
opinion.
3 Latin American countries, such
as Brazil, have no specific combination
product regulations. Sponsor applications
for these products currently fall under
Brazilian, Federal Laws No. 5.991/73 and

6.360/76 and ANVISA’s (the Brazilian National Health Surveillance Agency) Decree
No. 79.094/77 which regulates drugs and
medical devices. Law No 5.991/73 outlines
the requirements for what is considered a
product intended for medicinal purposes,
those that are medical devices, and those
that may warrant a pre-review by the Brazilian Ministry of Health and ANVISA.
4

Get engaged early with any potentialcountry where you plan to do commerce.

Gaining clarity on national requirements
may not be enough. The sponsoring company may need to drill down to the regional
and local jurisdictions to fully understand
all requirements and nuances. This level of
granularity is especially important when
conducting clinical trials overseas with clinical trial materials made in another country.

In these cases, import/export laws must be
considered and planned. This is where having regionally deployed personnel (“boots
on the ground”) are effective to navigate the
regulatory waters of local jurisdiction.

3. Develop an appropriate cGMPquality compliance strategy. From a qualitysystems standpoint, combination productsshould be viewed holistically as a “system”in which both constituent parts must havesuitable quality system requirements inplace, be it manufactured in same facility,(virtual sourcing). We find through variousFDA Form 483(s), Warning Letters andother recent stark reminders that the devel-opment and understanding of a combinationproduct is sometimes not in synch withcGMP manufacturing strategy. For example,in 2014, the FDA issued a Warning Letterto Amgen due to a June 2014 inspectionrelated to the PROLIA prefilled syringeand needle guard, EN-BREL lyophilized vial anddiluent with vial adaptor,and Enbrel prefilled syringewith “SureClick 1.5” autoinjector.
5 Deficiencies citedwere primarily in the qualitysystem element areas of de-sign, change, and purchasingcontrols. The interpretationof this Warning Lettersuggests that systems needto be developed and actedon for both device and phar-maceutical/biologic types.

The letter also infers that
legacy combination products still on the market may
be held to a more rigorous
standard in the near future,
including the retrospective
application of medical device and/or pharmaceutical
quality system requirements.

The Quality ManagementSystem (QMS) should bederived by a blended orbolt-on approach. If thesponsor is a pharmaceuticalcompany that developscombination products and conducts or pro-vides oversight for device operations, buildthose requirements into the pharma-basedmodel for complete regulatory compliancecoverage. Likewise, if the sponsor is a devicemanufacturer that conducts or providesoversight for pharma operations, includethe device requirements. Coach people onthe idea that both worlds are not mutuallyexclusive. Strip the label off the (device ordrug) regulation and focus on the actualintent of requests in the requirement.
4. Implement a design freeze during thecombination product development pro-cess. Pharma and biologics companies arenot device companies: many are unfamiliarwith the concept of a “design freeze.” Thatthe point in the product development lifecycle at which the actual design has beenformally approved and product changesprohibited, unless initiated through thedesign control process. Knowing when tofreeze design during combination productThe impact of regulatory uncertainty canbe reduced by pursuing development,understanding the regulatory landscape, aswell as developing a regulatory compliancestrategy appropriate for the combinationproduct as a “system.”

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